Hypoxia and HIF in Tumor-Associated Macrophage Driven Tumor Progression

描述(由申请人提供)：慢性炎症长期以来一直与癌症发展的风险增加有关。例如，溃疡性结肠炎患者患结直肠癌的风险增加。肿瘤相关巨噬细胞(TAMs)与先天性免疫系统、慢性炎症和肿瘤发生有关，因为肿瘤中巨噬细胞的出现与患者预后不良、淋巴结受累增加和远处转移有关。TAMs是一种异质性的髓系细胞群，它主要渗透到实体瘤内的缺氧区，在那里它们分泌生长因子和细胞因子，刺激血管生成，促进侵袭和/或转移。一些研究表明，氧敏感的低氧诱导因子(HIF)转录调节因子控制对低氧的反应。特别是，在多种人类癌症中，TAMS中HIF-2的高表达与预后不良和高级别肿瘤相对应。巨噬细胞中HIF-2的特异性缺失抑制了结肠炎相关性结肠癌小鼠模型的原发肿瘤负担。HIF-2缺乏的巨噬细胞在体外表达低水平的介导血管生成和侵袭的蛋白质。这一提议的中心假设是，缺氧TAM需要HIF-2来表达促进肿瘤血管生成和转移的关键因子，从而推动肿瘤进展。基于这一假设，我将追求两个具体目标。具体目标1：在结肠炎相关性结肠癌的炎性小鼠模型中，确定髓系特异性HIF-2信号在促血管生成因子分泌中的作用。特定目的2：确定巨噬细胞中HIF-2的缺失如何抑制结肠癌小鼠模型中的肿瘤生长和转移。为了完成这些研究，我将结合细胞生物学、生物化学、免疫组织化学、活体成像、遗传学和动物建模的体外和体内方法。本研究的目的是阐明HIF-2在天然免疫系统中表达的潜在机制，提高我们对缺氧如何调控炎症相关癌症以及肿瘤微环境在促进肿瘤进展中所起的独特作用的理解，从而找到新的治疗靶点，从而促进结肠癌的新治疗。 公共卫生相关性：结直肠癌(CRC)是美国主要的死亡原因之一，现有的治疗方法包括手术、放射和化疗。某些慢性炎症状态会增加一个人患结直肠癌的风险，尽管有非常令人信服的证据表明炎症在肿瘤进展中起着直接作用，但潜在的机制尚未完全阐明。因此，我建议调查慢性炎症和癌症发展之间的关系，以促进新的治疗靶点的确定和进展。

DESCRIPTION (provided by applicant): Chronic inflammation has long been associated with increased risk of cancer development. For example, patients with ulcerative colitis have an increased risk of developing colorectal cancer. Tumor-associated macrophages (TAMs) have been implicated in connecting the innate immune system, chronic inflammation and tumorigenesis, as the appearance of macrophages in tumors corelates with poor patient prognosis, increased lymph node involvement, and distant metastases. TAMs are a heterogeneous myeloid population that infiltrates predominantly hypoxic regions within solid tumors, where they secrete growth factors and cytokines that stimulate angiogenesis and facilitate invasion and/or metastasis. Several studies have implicated the oxygen-sensitive hypoxia inducible factor (HIF) transcriptional regulators in controlling TAM response to hypoxia. In particular, elevated expression of HIF-2¿ in TAMs corresponds with poor prognosis and high-grade tumors in a variety of human cancers. Specific deletion of HIF-2¿ in macrophages suppresses primary tumor burden in a mouse model of colitis-associated colon carcinoma. HIF-2¿ deficient macrophages express reduced levels of proteins mediating angiogenesis and invasion in vitro. The central hypothesis of this proposal is that HIF-2¿ is required for hypoxic TAMs to express critical factors that promote tumor angiogenesis and metastasis, and thereby drive tumor progression. Based on this hypothesis, I will pursue two specific aims. Specific Aim 1: To determine the role of myeloid-specific HIF-2¿ signaling in the secretion of pro-angiogenic factors in an inflammatory murine model of colitis-associated colon cancer. Specific Aim 2: To determine how loss of HIF-2¿ in macrophages supreses tumor progresion and metastasis in a murine model of colon cancer. To complete these studies I will combine in vitro and in vivo methods of cell biology, biochemistry, immunohistochemistry, live imaging, genetics, and animal modeling. The objective of this proposal is to elucidate the underlying mechanisms of HIF-2¿ expression in the innate immune system, improve our understanding of how hypoxia regulates inflammation-associated cancer, and the unique role tumor microenvironment plays in fueling tumor progression and thereby identify novel therapeutic targets which will facilitate new treatments for colon cancer. PUBLIC HEALTH RELEVANCE: Colorectal cancer (CRC) is one of the leading causes of death in the United States with available treatments consisting of surgery, radiation, and chemotherapy. Certain states of chronic inflammation can increase a person's risk of developing CRC and although there is very convincing evidence that inflammation plays a direct role in tumor progression, the underlying mechanisms are not fully elucidated. I therefore propose to investigate the relationship between chronic inflammation and cancer development in order to facilitate the identification and advancement of novel therapeutic targets.